Search

Your search keyword '"Miedzybrodzka, Zosia"' showing total 11 results
Start Over Author "Miedzybrodzka, Zosia" Topic mutation
11 results on '"Miedzybrodzka, Zosia"'

1. The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse.

Author

Collinson JM, Lindström NO, Neves C, Wallace K, Meharg C, Charles RH, Ross ZK, Fraser AM, Mbogo I, Oras K, Nakamoto M, Barker S, Duce S, Miedzybrodzka Z, and Vargesson N

Subjects
Animals, Axons, Charcot-Marie-Tooth Disease genetics, Charcot-Marie-Tooth Disease pathology, Chick Embryo, Chromosome Mapping, Clubfoot pathology, Disease Models, Animal, Female, Hindlimb abnormalities, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Motor Neurons pathology, Muscle, Skeletal abnormalities, Muscle, Skeletal innervation, Peroneal Nerve abnormalities, Phenotype, Pregnancy, Receptor, EphA4 deficiency, Receptor, EphA4 genetics, Sciatic Nerve abnormalities, Up-Regulation, Charcot-Marie-Tooth Disease embryology, Clubfoot embryology, Clubfoot genetics, Lim Kinases genetics, Mutation
Abstract

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. The pma mutation was mapped and a candidate gene encoding LIM-domain kinase 1 ( Limk1 ) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation of Limk1 by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Published
2018
Full Text
View/download PDF

2. Mutation of genes controlling mRNA metabolism and protein synthesis predisposes to neurodevelopmental disorders.

Author

Sartor F, Anderson J, McCaig C, Miedzybrodzka Z, and Müller B

Subjects
Active Transport, Cell Nucleus genetics, Humans, Models, Genetic, Neurodevelopmental Disorders metabolism, RNA Stability genetics, RNA, Messenger metabolism, Signal Transduction genetics, Genetic Predisposition to Disease genetics, Mutation, Neurodevelopmental Disorders genetics, Protein Biosynthesis genetics, RNA, Messenger genetics
Abstract

Brain development is a tightly controlled process that depends upon differentiation and function of neurons to allow for the formation of functional neural networks. Mutation of genes encoding structural proteins is well recognized as causal for neurodevelopmental disorders (NDDs). Recent studies have shown that aberrant gene expression can also lead to disorders of neural development. Here we summarize recent evidence implicating in the aetiology of NDDs mutation of factors acting at the level of mRNA splicing, mRNA nuclear export, translation and mRNA degradation. This highlights the importance of these fundamental processes for human health and affords new strategies and targets for therapeutic intervention., (© 2015 Authors; published by Portland Press Limited.)

Published
2015
Full Text
View/download PDF

3. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE.

Author

Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, Evans DG, Izatt L, Eeles RA, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Tischkowitz M, Douglas F, Hodgson S, Walker L, Porteous ME, Morrison PJ, Side LE, Kennedy MJ, Houghton C, Donaldson A, Rogers MT, Dorkins H, Miedzybrodzka Z, Gregory H, Eason J, Barwell J, McCann E, Murray A, Antoniou AC, and Easton DF

Subjects
Adult, Aged, Confounding Factors, Epidemiologic, Female, Genetic Predisposition to Disease, Humans, Incidence, Ireland epidemiology, Kaplan-Meier Estimate, Middle Aged, Odds Ratio, Ovarian Neoplasms prevention & control, Ovariectomy, Primary Prevention methods, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors, Salpingectomy, Surveys and Questionnaires, United Kingdom epidemiology, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Heterozygote, Mutation, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Background: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles., Methods: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided., Results: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02)., Conclusions: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

Published
2013
Full Text
View/download PDF

4. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.

Author

Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, Rodrigues DN, Renwick A, Seal S, Ramsay E, Duarte Sdel V, Rivas MA, Warren-Perry M, Zachariou A, Campion-Flora A, Hanks S, Murray A, Ansari Pour N, Douglas J, Gregory L, Rimmer A, Walker NM, Yang TP, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Eccles D, Evans DG, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L, Gore M, Houlston R, Brown MA, Caufield MJ, Deloukas P, McCarthy MI, Todd JA, Turnbull C, Reis-Filho JS, Ashworth A, Antoniou AC, Lord CJ, Donnelly P, and Rahman N

Subjects
Alleles, Cluster Analysis, Exons, Female, Humans, Isoenzymes genetics, Lymphocytes metabolism, Protein Phosphatase 2C, Sequence Analysis, DNA, Tumor Suppressor Protein p53 metabolism, Breast Neoplasms genetics, Genetic Predisposition to Disease genetics, Mosaicism, Mutation, Ovarian Neoplasms genetics, Phosphoprotein Phosphatases genetics
Abstract

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Published
2013
Full Text
View/download PDF

5. Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Author

Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L, Healey S, Lee A, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Cattaneo E, Barile M, Pensotti V, Pasini B, Dolcetti R, Giannini G, Putignano AL, Varesco L, Radice P, Mai PL, Greene MH, Andrulis IL, Glendon G, Ozcelik H, Thomassen M, Gerdes AM, Kruse TA, Birk Jensen U, Crüger DG, Caligo MA, Laitman Y, Milgrom R, Kaufman B, Paluch-Shimon S, Friedman E, Loman N, Harbst K, Lindblom A, Arver B, Ehrencrona H, Melin B, Nathanson KL, Domchek SM, Rebbeck T, Jakubowska A, Lubinski J, Gronwald J, Huzarski T, Byrski T, Cybulski C, Gorski B, Osorio A, Ramón y Cajal T, Fostira F, Andrés R, Benitez J, Hamann U, Hogervorst FB, Rookus MA, Hooning MJ, Nelen MR, van der Luijt RB, van Os TA, van Asperen CJ, Devilee P, Meijers-Heijboer HE, Gómez Garcia EB, Peock S, Cook M, Frost D, Platte R, Leyland J, Evans DG, Lalloo F, Eeles R, Izatt L, Adlard J, Davidson R, Eccles D, Ong KR, Cook J, Douglas F, Paterson J, Kennedy MJ, Miedzybrodzka Z, Godwin A, Stoppa-Lyonnet D, Buecher B, Belotti M, Tirapo C, Mazoyer S, Barjhoux L, Lasset C, Leroux D, Faivre L, Bronner M, Prieur F, Nogues C, Rouleau E, Pujol P, Coupier I, Frénay M, Hopper JL, Daly MB, Terry MB, John EM, Buys SS, Yassin Y, Miron A, Goldgar D, Singer CF, Tea MK, Pfeiler G, Dressler AC, Hansen Tv, Jønson L, Ejlertsen B, Barkardottir RB, Kirchhoff T, Offit K, Piedmonte M, Rodriguez G, Small L, Boggess J, Blank S, Basil J, Azodi M, Toland AE, Montagna M, Tognazzo S, Agata S, Imyanitov E, Janavicius R, Lazaro C, Blanco I, Pharoah PD, Sucheston L, Karlan BY, Walsh CS, Olah E, Bozsik A, Teo SH, Seldon JL, Beattie MS, van Rensburg EJ, Sluiter MD, Diez O, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Ruehl I, Varon-Mateeva R, Kast K, Deissler H, Niederacher D, Arnold N, Gadzicki D, Schönbuchner I, Caldes T, de la Hoya M, Nevanlinna H, Aittomäki K, Dumont M, Chiquette J, Tischkowitz M, Chen X, Beesley J, Spurdle AB, Neuhausen SL, Chun Ding Y, Fredericksen Z, Wang X, Pankratz VS, Couch F, Simard J, Easton DF, and Chenevix-Trench G

Subjects
Adult, Aged, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 6 genetics, Female, Heterozygote, Humans, Middle Aged, Polymorphism, Single Nucleotide genetics, Risk Factors, Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Chromosomes, Human genetics, Genetic Predisposition to Disease, Mutation genetics
Abstract

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Published
2011
Full Text
View/download PDF

6. Probability estimation models for prediction of BRCA1 and BRCA2 mutation carriers: COS compares favourably with other models.

Author

Roudgari H, Miedzybrodzka ZH, and Haites NE

Subjects
Area Under Curve, Female, Genetic Counseling, Humans, Incidence, Middle Aged, Pedigree, Predictive Value of Tests, Prevalence, ROC Curve, Risk Assessment, Scotland epidemiology, Sensitivity and Specificity, Software, BRCA1 Protein genetics, BRCA2 Protein genetics, Genes, BRCA1, Genes, BRCA2, Models, Genetic, Models, Statistical, Mutation
Abstract

Background: Accurate risk assessment is essential to genetic counselling for a family history of cancer. Several empiric and computer-based risk assessment models have been developed to estimate a counselee's probability of being a carrier of mutation in BRCA1 and/or 2 genes, and to predict the risk of developing breast cancer. The COS model was developed from the better-known BRCAPro model to estimate risk of carriage of BRCA1 or 2 mutation. The COS model remains to be validated in a population discrete from that used for its development., Methods: Four probability estimation models including COS, Manchester scoring system (MSS), BOADICEA and Tyrer-Cuzick (T-C) were applied to 275 Scottish families tested for BRCA1/2 mutations ascertained through regional genetics centres to ascertain models' sensitivity, specificity and accuracy. A subset of 130 families from Grampian (North and Northeast Scotland) was used to assess the models' ability to estimate the prevalence of BRCA1/2 mutation carriers. Sensitivity, specificity and ROC plots were used to ascertain models' individual performance, in terms of number of cancer cases, type of cancer and age of diagnosis of breast cancer., Results: The COS and MSS models demonstrated the greatest sensitivities and area under ROC curves for the majority of family structures. They also showed the highest sensitivities (91-92%) and AUCs (76-78%) for the entire dataset overall. However, BOADICEA and T-C had the highest specificities for the majority of the family structures. BOADICEA and T-C generated the best estimates for the prevalence of mutations in the population; BOADICEA was more accurate for BRCA1 and T-C for BRCA2., Conclusion: The COS and MSS models are the most effective models for use in clinical practice to select families for mutation analysis, but BOADICEA and T-C are more accurate for estimating mutation prevalence within a population.

Published
2008
Full Text
View/download PDF

7. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export.

Author

Legati, Andrea, Giovannini, Donatella, Nicolas, Gaël, López-Sánchez, Uriel, Quintáns, Beatriz, Oliveira, João RM, Sears, Renee L, Ramos, Eliana Marisa, Spiteri, Elizabeth, Sobrido, María-Jesús, Carracedo, Ángel, Castro-Fernández, Cristina, Cubizolle, Stéphanie, Fogel, Brent L, Goizet, Cyril, Jen, Joanna C, Kirdlarp, Suppachok, Lang, Anthony E, Miedzybrodzka, Zosia, Mitarnun, Witoon, Paucar, Martin, Paulson, Henry, Pariente, Jérémie, Richard, Anne-Claire, Salins, Naomi S, Simpson, Sheila A, Striano, Pasquale, Svenningsson, Per, Tison, François, Unni, Vivek K, Vanakker, Olivier, Wessels, Marja W, Wetchaphanphesat, Suppachok, Yang, Michele, Boller, Francois, Campion, Dominique, Hannequin, Didier, Sitbon, Marc, Geschwind, Daniel H, Battini, Jean-Luc, and Coppola, Giovanni

Subjects
Humans, Brain Diseases, Metabolic, Inborn, Neurodegenerative Diseases, Calcinosis, Genetic Predisposition to Disease, Receptors, G-Protein-Coupled, Receptors, Virus, Pedigree, DNA Mutational Analysis, Lod Score, Mutation, Missense, Middle Aged, Female, Male, Genetic Association Studies, HEK293 Cells, Xenotropic and Polytropic Retrovirus Receptor, Neurosciences, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.

Published
2015

8. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O’Mara, Tracy A., Dennis, Joe, Tyrer, Jonathan P., Barnes, Daniel R., McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K., Adank, Muriel A., Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Bertrand, Ophélie, Caputo, Sandrine, Dupré, Anaïs, le Mentec, Marine, Belotti, Muriel, Birot, Anne-Marie, Buecher, Bruno, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Houdayer, Claude, Moncoutier, Virginie, de Pauw, Antoine, Saule, Claire, Sinilnikova, Olga, Mazoyer, Sylvie, Damiola, Francesca, Barjhoux, Laure, Verny-Pierre, Carole, Léone, M. lanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Caron, Olivier, Guillaud-Bataille, Marine, Bressac-de-Paillerets, Brigitte, Bignon, Yves- Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Noguchi, Tetsuro, Popovici, Cornel, Sobol, Hagay, Bourdon, Violaine, Remenieras, Audrey, Noguès, Catherine, Coupier, Isabelle, Pujol, Pascal, Dumont, Aurélie, Révillion, Françoise, Adenis, Claude, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Leroux, Dominique, Dreyfus, H. lène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Mari, V. ronique, Vénat-Bouvet, Laurence, Delnatte, Capucine, Bézieau, Stéphane, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Sokolowska, Johanna, Bronner, Myriam, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Ong, Kai-ren, Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brewer, Carole, Davidson, Rosemarie, Izatt, Louise, Brady, Angela, Barwell, Julian, Adlard, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Eeles, Rosalind A., Cook, Jackie, Snape, Katie, Eccles, Diana, Murray, Alex, McCann, Emma, Collée, J. Margriet, Conroy, Don M., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., He, Wei, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Horcasitas, Darling J., Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Fox, Stephen, Campbell, Ian, Spurdle, Amanda, Webb, Penny, de Fazio, Anna, Tassell, Margaret, Kirk, Judy, Lindeman, Geoff, Price, Melanie, Southey, Melissa, Milne, Roger, Deb, Sid, Bowtell, David, van der Hout, Annemieke H., van den Ouweland, Ans M. W., Mensenkamp, Arjen R., van Deurzen, Carolien H. M., Kets, Carolien M., Seynaeve, Caroline, van Asperen, Christi J., Aalfs, Cora M., Gómez Garcia, Encarna B., van Leeuwen, Flora E., de Bock, G. H., Meijers-Heijboer, Hanne E. J., Obdeijn, Inge M., Gille, J. J. P., Oosterwijk, Jan C., Wijnen, Juul T., van der Kolk, Lizet E., Hooning, Maartje J., Ausems, Margreet G. E. M., Mourits, Marian J. E., Blok, Marinus J., Rookus, Matti A., van der Luijt, Rob B., van Cronenburg, T. C. T. E. F., van der Pol, Carmen C., Russell, Nicola S., Siesling, Sabine, Overbeek, Lucy, Wijnands, R., de Lange, Judith L., Clarke, Christine, Graham, Dinny, Sachchithananthan, Mythily, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Jager, Agnes, Jakubowska, Anna, James, Paul A., Jensen, Uffe Birk, John, Esther M., Jones, Michael E., Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W., Laitman, Yael, Lambrechts, Diether, le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T., Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L., Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., O’Brien, Katie M., Olopade, Olufunmilayo I., Olson, Janet E., Olsson, H. kan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Phillips, Kelly-Anne, Polley, Eric C., Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P., Santella, Regina, Scheuner, Maren T., Schmidt, Marjanka K., Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Teulé, Alex, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Trainer, Alison H., Truong, Thérèse, Tung, Nadine, Vachon, Celine M., Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Park, Sue K., Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K., Couch, Fergus J., Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F., Andrieu, Nadine, Antoniou, Antonis C., German Cancer Research Center, National Health and Medical Research Council (Australia), United States of Department of Health & Human Services, National Institute for Health Research (Reino Unido), French National Cancer Institute, Ligue Nationale Contre le Cancer (Francia), Cancer Research UK (Reino Unido), Unión Europea. Comisión Europea, Canadian Institutes of Health Research, Cancer Council New South Wales (Australia), KWF Kankerbestrijding, Instituto de Salud Carlos III, Xunta de Galicia (España), Ministerio de Sanidad, Política Social e Igualdad (España), Helmholtz Association, California Breast Cancer Research Program, Federal Ministry of Education & Research (Alemania), Government of Netherlands, Russian Foundation for Basic Research, O’Mara, Tracy A. [0000-0002-5436-3232], Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P. [0000-0003-3724-4757], Barnes, Daniel R. [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Ahearn, Thomas [0000-0003-0771-7752], Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Barrowdale, Daniel [0000-0003-1661-3939], Becher, Heko [0000-0002-8808-6667], Bernstein, Leslie [0000-0002-7692-6518], Bojesen, Stig E. [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Chanock, Stephen J. [0000-0002-2324-3393], Chung, Wendy K. [0000-0003-3438-5685], Claes, Kathleen B. M. [0000-0003-0841-7372], Collée, J. Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Eliassen, A. Heather [0000-0002-3961-6609], Fritschi, Lin [0000-0002-7692-3560], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Gayther, Simon A. [0000-0001-7937-5443], Giles, Graham G. [0000-0003-4946-9099], Greene, Mark H. [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Hart, Steven N. [0000-0001-7714-2734], He, Wei [0000-0003-0161-3274], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J. [0000-0001-8397-4078], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A. [0000-0002-4361-4657], Jensen, Uffe Birk [0000-0002-6205-6355], Jones, Michael E. [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Kurian, Allison W. [0000-0002-6175-9470], Lambrechts, Diether [0000-0002-3429-302X], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John W. M. [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Milne, Roger L. [0000-0001-5764-7268], Nathanson, Katherine L. [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I. [0000-0002-9936-1599], Olson, Janet E. [0000-0003-4944-7789], Ottini, Laura [0000-0001-8030-0449], Parsons, Michael T. [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Pharoah, Paul D. P. [0000-0001-8494-732X], Punie, Kevin [0000-0002-1162-7963], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Sandler, Dale P. [0000-0002-6776-0018], Schmidt, Marjanka K. [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Toland, Amanda E. [0000-0002-0271-1792], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M. [0000-0002-1962-9322], Vega, Ana [0000-0002-7416-5137], Vijai, Joseph [0000-0002-7933-151X], Weitzel, Jeffrey N. [0000-0001-6714-092X], Wolk, Alicja [0000-0001-7387-6845], Yadav, Siddhartha [0000-0003-4630-9903], Yannoukakos, Drakoulis [0000-0001-7509-3510], Ziogas, Argyrios [0000-0003-4529-3727], Zorn, Kristin K. [0000-0003-2143-8979], Park, Sue K. [0000-0001-5002-9707], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Becher, Heiko [0000-0002-8808-6667], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, German Cancer Research Center (DKFZ), National Health and Medical Research Council of Australia, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, National Institute for Health Research (NIHR), Institut National du Cancer (INCA) France, Ligue nationale contre le cancer, Cancer Research UK, European Commision, Canadian Institutes of Health Research (CIHR), Cancer Council New South Wales, Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud, Xunta de Galicia, Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain, Fondo de Investigacion Sanitario, California Breast Cancer Research Fund, Federal Ministry of Education & Research (BMBF), Netherlands Government, Russian Foundation for Basic Research (RFBR), O'Mara, Tracy A [0000-0002-5436-3232], Tyrer, Jonathan P [0000-0003-3724-4757], Barnes, Daniel R [0000-0002-3781-7570], Andrulis, Irene L [0000-0002-4226-6435], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Dunning, Alison M [0000-0001-6651-7166], Eliassen, A Heather [0000-0002-3961-6609], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Hart, Steven N [0000-0001-7714-2734], Hulick, Peter J [0000-0001-8397-4078], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kurian, Allison W [0000-0002-6175-9470], Martens, John WM [0000-0002-3428-3366], Milne, Roger L [0000-0001-5764-7268], Nathanson, Katherine L [0000-0002-6740-0901], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Janet E [0000-0003-4944-7789], Parsons, Michael T [0000-0003-3242-8477], Pharoah, Paul DP [0000-0001-8494-732X], Sandler, Dale P [0000-0002-6776-0018], Schmidt, Marjanka K [0000-0002-2228-429X], Toland, Amanda E [0000-0002-0271-1792], Vachon, Celine M [0000-0002-1962-9322], Weitzel, Jeffrey N [0000-0001-6714-092X], Zorn, Kristin K [0000-0003-2143-8979], Park, Sue K [0000-0001-5002-9707], Easton, Douglas F [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Coignard J] Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France. Institut Curie Paris, Paris, France. Mines ParisTech Fontainebleau, Paris, France. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. PSL University Paris, Paris, France. Paris Sud University, Orsay, France. [Lush M, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Beesley J, O'Mara TA] Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Lopez-Fernández A] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, ​Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Clinical Genetics, Medical Oncology, Pathology, and Radiology & Nuclear Medicine

Subjects
0301 basic medicine, Linkage disequilibrium, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], 45/43, General Physics and Astronomy, Genome-wide association study, Linkage Disequilibrium, Breast cancer, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, Genotype, breast neoplasms, Medicine and Health Sciences, 631/208/68, skin and connective tissue diseases, Cancer genetics, adult, alleles, BRCA1 protein, BRCA2 protein, female, genetic predisposition to disease, genome-wide association study, genotype, humans, linkage disequilibrium, middle aged, mutation, quantitative trait loci, risk factors, polymorphism, single nucleotide, HEBON Investigators, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], BRCA1 Protein, Genetic Predisposition to Disease/genetics, article, Single Nucleotide, Middle Aged, BRCA2 Protein/genetics, 3. Good health, Mama - Càncer - Factors de risc, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Genome-Wide Association Study/methods, Medical genetics, Female, Medical Genetics, 692/499, Adult, medicine.medical_specialty, 45/61, Science, 3122 Cancers, Population, Quantitative Trait Loci, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], ABCTB Investigators, 631/67/2324, Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Càncer de mama, GEMO Study Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, EMBRACE Collaborators, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], Alleles, Medicinsk genetik, BRCA2 Protein, Mutació (Biologia), General Chemistry, 631/67/1347, Genotype frequency, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, BRCA1 Protein/genetics, 3111 Biomedicine, KConFab Investigators, Quantitative Trait Loci/genetics, Genètica, Genome-Wide Association Study
Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P, Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Published
2021

9. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author

Blein, Sophie, Bardel, Claire, Danjean, Vincent, Mcguffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B., Soucy, Penny, Terry, Mary Beth, Chung, Wendy K., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Gerdes, Anne Marie, Ejlertsen, Bent, Nielsen, Finn C., Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Conejero, Raquel Andrés, Segota, Ena, Weitzel, Jeffrey N., Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L., Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D. Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E., Kennedy, M. John, Tischkowitz, Marc, Rogers, Mark T., Porteous, Mary E., Morrison, Patrick J., Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K., Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon Mateeva, Raymonda, Schmutzler, Rita K., Preisler Adams, Sabine, Markov, Nadja Bogdanova, Wang Gohrke, Shan, de Pauw, Antoine, Lefol, Cédrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, Dreyfus, Hélène, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valérie, Sornin, Valérie, Bignon, Yves Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, Disilvestro, Paul A., de la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Jager, Agnes, van den Ouweland, Ans M. W., Kets, Carolien M., Aalfs, Cora M., van Leeuwen, Flora E., Hogervorst, Frans B. L., Meijers Heijboer, Hanne E. J., Oosterwijk, Jan C., van Roozendaal, Kees E. P., Rookus, Matti A., Devilee, Peter, van der Luijt, Rob B., Olah, Edith, Diez, Orland, Teulé, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesús, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska Bieniek, Katarzyna, Agnarsson, Bjarni A., Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R., Spurdle, Amanda B., Foulkes, William, Olswold, Curtis, Lindor, Noralane M., Pankratz, Vernon S., Szabo, Csilla I., Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy Kheng, Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L., Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Caligo, Maria A., Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I., Nussbaum, Robert L., Ramus, Susan J., Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy R., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Orsulic, Sandra, Stoppa Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J., Offit, Kenneth, Easton, Douglas F., Chenevix Trench, Georgia, Antoniou, Antonis C., Mazoyer, Sylvie, Phelan, Catherine M., Sinilnikova, Olga M., Cox, David G., Angelakos, Maggie, Maskiell, Judi, Dite, Gillian, Tsimiklis, Helen, Rudaitis, Vilius, Griškevicius, Laimonas, Eglitis, Drs Janis, Krilova, Anna, Stengrevics, Aivars, Ding, Chun, Steele, Linda, Barroso, Alicia, Alonso, Rosario, Pita, Guillermo, Viel, Alessandra, della Puppa, Lara, Barile, Monica, Tommasi, Stefania, Pilato, Brunella, Lambo, Rossana, Martayan, Aline, Tibiletti, Maria Grazia, Ellis, Steve, Fineberg, Elena, Miedzybrodzka, Zosia, Gregory, Helen, Jeffers, Lisa, Ong, Kai Ren, Hoffman, Jonathan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Mccann, Emma, Barton, David, Drummond, Sarah, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Jacobs, Chris, Langman, Caroline, Dorkins, Huw, Serra Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Collier, Rebecca, Claber, Oonagh, Jobson, Irene, Mcleod, Diane, Halliday, Dorothy, Durell, Sarah, Stayner, Barbara, Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Quarrell, Oliver, Bardsley, Cathryn, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Lucassen, Anneke, Crawford, Gillian, Mcbride, Donna, Smalley, Sarah, Weaver, Jo Ellen, Bove, Betsy, Verny Pierre, Carole, Calender, Alain, Giraud, Sophie, Léone, Mélanie, Gauthier Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Belotti, Muriel, Tirapo, Carole, Bressac de Paillerets, Brigitte, Caron, Olivier, Handallou, Sandrine, Hardouin, Agnès, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Eisinger, François, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Frénay, Marc, Vénat Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Sokolowska, Johanna, Bronner, Myriam, Collonge Rame, Marie Agnès, Damette, Alexandre, Lynch, Henry T., Snyder, Carrie L., Muranen, Taru A., Blomqvist, Drs Carl, Aaltonen, Kirsimari, Erkkilä, Irja, Palola, Virpi, Verhoef, S., Schmidt, M. K., de Lange, J. L., Wijnands, R., Collée, J. M., Hooning, M. J., Seynaeve, C., van Deurzen, C. H. M., Obdeijn, I. M., van Asperen, C. J., Wijnen, J. T., Tollenaar, R. A. E. M., van Cronenburg, T. C. T. E. F., Mensenkamp, A. R., Ausems, M. G. E. M., van Os, T. A. M., Gille, J. J. P., Waisfisz, Q., Gómez Garcia, E. B., Blok, M. J., van der Hout, A. H., Mourits, M. J., de Bock, G. H., Vasen, H. F., Siesling, S., Overbeek, L. I. H., Papp, Janos, Vaszko, Tibor, Bozsik, Aniko, Pocza, Timea, Franko, Judit, Balogh, Maria, Domokos, Gabriella, Ferenczi, Judit, Balmaña, J., Capella, Gabriel, Dumont, Martine, Tranchant, Martine, Peixoto, Ana, Santos, Catarina, Rocha, Patrícia, Pinto, Pedro, Thorne, Heather, Niedermayr, Eveline, Foretova, Lenka, Machackova, Eva, Zikan, Michal, Pohlreich, Petr, Kleibl, Zdenek, Dishon, Sara, Lejbkowicz, Flavio, Pinchev, Mila, Senter, Leigha, Sweet, Kevin, Craven, Caroline, O'Conor, Michelle, Borg, Ake, Olsson, Håkan, Jernström, Helena, Henriksson, Karin, Harbst, Katja, Soller, Maria, Kristoffersson, Ulf, Öfverholm, Anna, Nordling, Margareta, Karlsson, Per, Einbeigi, Zakaria, von Wachenfeldt, Anna, Liljegren, Annelie, Bustinza, Gisela Barbany, Rantala, Johanna, Ardnor, Christina Edwinsdotter, Emanuelsson, Monica, Ehrencrona, Hans, Pigg, Maritta Hellström, Stenmark Askmalm, Marie, Liedgren, Sigrun, Zvocec, Cecilia, Niu, Qun, Seldon, Joyce, Kwan, Lorna, Crawford, Beth, Loranger, Kate, Mak, Julie, Stewart, Nicola, Lee, Robin, Blanco, Amie, Conrad, Peggy, Chan, Salina, Pharoah, Paul D. P., Gayther, Simon, Pye, Carole, Harrington, Patricia, Wozniak, Eva, Lindeman, Geoffrey, Harris, Marion, Delatycki, Martin, Sawyer, Sarah, Driessen, Rebecca, Thompson, Ella, Breast Cancer Family Registry, Null, Embrace, Null, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Medical Oncology, Clinical Genetics, Radiotherapy, MUMC+: DA KG Lab Specialisten (9), Klinische Genetica, Genetica & Celbiologie, RS: FHML non-thematic output, [ 1 ] Univ Lyon 1, Ctr Rech Cancerol Lyon, CNRS, INSERM U1052,UMR5286, F-69365 Lyon, France [ 2 ] Univ Lyon, F-69000 Lyon, France [ 3 ] Univ Lyon 1, F-69100 Villeurbanne, France [ 4 ] Univ Lyon 1, CNRS, Lab Biometrie & Biol Evolut LBBE Biometrie & Bio, UMR 5558, F-69622 Villeurbanne, France [ 5 ] Univ Grenoble Alpes, Lab Informat Grenoble LIG, Equipe Projet Multiprogrammat & Ordonnancement Re, UMR 5217, F-38041 Grenoble, France [ 6 ] INRIA Rhone Alpes, Equipe Projet MOAIS, F-38334 Saint Ismier, France [ 7 ] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England [ 8 ] QIMR Berghofer, Dept Genet & Computat Biol, Brisbane, Qld, Australia [ 9 ] Univ Laval, Ctr Hosp Univ Quebec, Ctr Rech, Charlesbourg, PQ, Canada [ 10 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA [ 11 ] Columbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10027 USA [ 12 ] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10027 USA [ 13 ] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA [ 14 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT USA [ 15 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 16 ] Vilnius State Univ, Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Vilnius, Lithuania [ 17 ] State Res Inst, Ctr Innovat Med, Dept Mol & Regenerat Med, Vilnius, Lithuania [ 18 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 19 ] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA [ 20 ] Univ Pretoria, Dept Genet, ZA-0028 Pretoria, South Africa [ 21 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 22 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark [ 23 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 24 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 25 ] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Madrid, Spain [ 26 ] Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain [ 27 ] Hosp Clin Univ Lozano Blesa, Med Oncol Serv, Zaragoza 50009, Spain [ 28 ] Holy Cross Hosp, Michael & Dianne Bienes Comprehens Canc Ctr, Ft Lauderdale, FL USA [ 29 ] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Div Clin Canc Genet, Duarte, CA 91010 USA [ 30 ] John Muir Med Ctr, Walnut Creek, CA USA [ 31 ] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Duarte, CA 91010 USA [ 32 ] Ist FIRC Oncol Mol IFOM, I-20139 Milan, Italy [ 33 ] Ist Nazl Tumori, IRCCS, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 34 ] Cogentech Canc Genet Test Lab, I-20139 Milan, Italy [ 35 ] Ctr Riferimento Oncol CRO, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 36 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 37 ] Ist Nazl Tumori, IRCCS, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 38 ] Azienda Osped Univ San Martino Genova, IST Ist Nazl Ric Cancro, IRCCS, Dept Epidemiol Prevent & Special Funct,Unit Hered, I-16132 Genoa, Italy [ 39 ] FiorGen Fdn Pharmacogen, I-50019 Sesto Fiorentino, Italy [ 40 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 41 ] Univ Roma La Sapienza, Dept Mol Med, I-00185 Rome, Italy [ 42 ] Aristotle Univ Thessaloniki, Papageorgiou Hosp, Sch Med, Dept Med Oncol, GR-54006 Thessaloniki, Greece [ 43 ] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens, Greece [ 44 ] Dana Farber Canc Inst, Boston, MA 02215 USA [ 45 ] Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, Heidelberg, Germany [ 46 ] St Michaels Hosp, Dept Clin Genet, Bristol BS2 8EG, Avon, England [ 47 ] Kennedy Galton Ctr, North West Thames Reg Genet Serv, Harrow, Middx, England [ 48 ] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England [ 49 ] Liverpool Womens NHS Fdn Trust, Merseyside & Cheshire Clin Genet Serv, Liverpool L8 7SS, Merseyside, England [ 50 ] Cent Manchester Univ Hosp, NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Genet Med, Manchester, Lancs, England [ 51 ] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England [ 52 ] Univ Southampton, Southampton Univ Hosp, NHS Trust, Fac Med, Southampton SO16 6YD, Hants, England [ 53 ] Newcastle Upon Tyne Hosp, NHS Trust, Int Ctr Life, Inst Human Genet,Northern Genet Serv, Newcastle Upon Tyne NE1 4EP, Tyne & Wear, England [ 54 ] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England [ 55 ] Leeds Teaching Hosp, NHS Trust, Old Med Sch, Yorkshire Reg Genet Serv, Leeds LS1 3EX, W Yorkshire, England [ 56 ] Univ Hosp Leicester, NHS Trust, Leicester Royal Infirm, Dept Clin Genet,Leicestershire Clin Genet Serv, Leicester LE1 5WW, Leics, England [ 57 ] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LE, England [ 58 ] Guys Hosp, Guys & St Thomas NHS Fdn Trust, Clin Genet Serv, London SE1 9RT, England [ 59 ] Great Ormond St Hosp Sick Children, NHS Trust, North East Thames Reg Genet Serv, London WC1N 3BH, England [ 60 ] Trinity Coll Dublin, Acad Unit Clin & Mol Oncol, Dublin 2, Ireland [ 61 ] St James Hosp, Med Oncol Serv, Dublin 8, Ireland [ 62 ] Cambridge Univ Hosp, Addenbrookes Hosp, NHS Fdn Trust, Addenbrookes Treatment Ctr,Dept Clin Genet,East A, Cambridge CB2 0QQ, England [ 63 ] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF14 4XW, S Glam, Wales [ 64 ] Western Gen Hosp, South East Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland [ 65 ] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Canc Res & Cell Biol, Belfast BT9 7AE, Antrim, North Ireland [ 66 ] Belfast City Hosp, Belfast Hlth & Social Care Trust, Dept Med Genet, Belfast BT9 7AB, Antrim, North Ireland [ 67 ] Inst Canc Res, Oncogenet Team, London SW7 3RP, England [ 68 ] Royal Marsden NHS Fdn Trust, London SW7 3RP, England [ 69 ] Yorkhill Hosp, Ferguson Smith Ctr Clin Genet, Glasgow G3 8SJ, Lanark, Scotland [ 70 ] Univ London St Georges Hosp, Dept Med Genet, South West Thames Reg Genet Serv, London SW17 0RE, England [ 71 ] Birmingham Womens Hosp, Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England [ 72 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA [ 73 ] MedStar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA [ 74 ] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium [ 75 ] Tech Univ Munich, Univ Hosp Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-81675 Munich, Germany [ 76 ] Univ Wurzburg, Inst Humangenet, Ctr Familial Breast & Ovarian Canc, Biozentrum,Dept Med Genet, D-97074 Wurzburg, Germany [ 77 ] Univ Hosp Cologne, Fac Med, Canc Ctr Cologne, CIO,Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany [ 78 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 79 ] Univ Heidelberg Hosp, Inst Human Genet, Dept Human Genet, Heidelberg, Germany [ 80 ] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany [ 81 ] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, D-40225 Dusseldorf, Germany [ 82 ] Hannover Med Sch, Ctr Pathol & Forens & Genet Med, Inst Cell & Mol Pathol, D-30625 Hannover, Germany [ 83 ] Univ Med Ctr Schleswig Holstein, Inst Human Genet, D-24105 Kiel, Germany [ 84 ] Tech Univ Dresden, Univ Hosp Carl Gustav Carus Dresden, Dept Gynecol & Obstet, D-01062 Dresden, Germany [ 85 ] Univ Med Ctr Schleswig Holstein, Dept Gynecol & Obstet, D-24105 Kiel, Germany [ 86 ] Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany [ 87 ] GC HBOC, Cologne, Germany [ 88 ] Univ Hosp Munster, Inst Human Genet, D-48149 Munster, Germany [ 89 ] Univ Hosp Ulm, Dept Gynecol & Obstet, Ulm, Germany [ 90 ] Inst Curie, Dept Tumor Biol, F-75248 Paris 05, France [ 91 ] Ctr Leon Berard, Unite Prevent & Epidemiol Genet, F-69008 Lyon, France [ 92 ] CHU Grenoble, Genet Clin, F-38043 Grenoble 9, France [ 93 ] Univ Grenoble 1, INSERM, Inst Albert Bonniot, U823, F-38706 La Tronche, France [ 94 ] Hop Rene Huguenin, Lab Oncogenet, F-92210 St Cloud, France [ 95 ] Univ Clermont Ferrand, Ctr Jean Perrin, Dept Oncogenet, F-63011 Clermont Ferrand, France [ 96 ] Royal Prince Alfred Hosp, Sydney Canc Ctr, Gynaecol Oncol, Camperdown, NSW 2050, Australia [ 97 ] Univ Sydney, Camperdown, NSW 2050, Australia [ 98 ] Univ N Carolina, Dept OB GYN, Gynecol Oncol Grp, Chapel Hill, NC 27599 USA [ 99 ] Roswell Pk Canc Inst, Gynecol Oncol Grp Stat & Data Ctr, Buffalo, NY 14263 USA [ 100 ] Brown Univ, Women & Infants Hosp, Providence, RI 02905 USA [ 101 ] Hlth Res Inst San Carlos Clin Hosp IdISSC, Mol Oncol Lab, Madrid 28040, Spain [ 102 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki 00029, Finland [ 103 ] Univ Helsinki, Cent Hosp, Biomedicum Helsinki, Helsinki 00029, Finland [ 104 ] Univ Helsinki, Cent Hosp, Biomedicum Helsinki 1, Dept Clin Genet, FIN-00290 Helsinki, Finland [ 105 ] Erasmus Univ, Med Ctr, Dept Med Oncol, Family Canc Clin, NL-3000 CA Rotterdam, Netherlands [ 106 ] Erasmus Univ, Med Ctr, Dept Clin Genet, Family Canc Clin, NL-3000 CA Rotterdam, Netherlands [ 107 ] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands [ 108 ] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands [ 109 ] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands [ 110 ] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands [ 111 ] Vrije Univ Amsterdam, Med Ctr Amsterdam, Dept Clin Genet, NL-1081 HV Amsterdam, Netherlands [ 112 ] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands [ 113 ] Maastricht Univ, Med Ctr, Dept Clin Genet, NL-6200 MD Maastricht, Netherlands [ 114 ] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Dept Human Genet, NL-2300 RC Leiden, Netherlands [ 115 ] Leiden Univ, Med Ctr, Dept Pathol, NL-2300 RC Leiden L1Q, Netherlands [ 116 ] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands [ 117 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 118 ] Univ Hosp Vall DHebron, Vall DHebron Inst Oncol VHIO, Vall DHebron Res Inst VHIR, Oncogenet Grp, Barcelona 08035, Spain [ 119 ] Univ Autonoma Barcelona, Barcelona 08035, Spain [ 120 ] Hosp Duran & Reynals, Catalan Inst Oncol, Inst Invest Biomed Bellvitge IDIBELL, Genet Counseling Unit,Hereditary Canc Program, Barcelona 08908, Spain [ 121 ] Hosp Duran & Reynals, Catalan Inst Oncol, Inst Invest Biomed Bellvitge IDIBELL, Mol Diagnost Unit,Hereditary Canc Program, Barcelona 08908, Spain [ 122 ] Pomeranian Med Univ, Fac Med & Dent, Dept Genet & Pathomorphol, PL-70111 Szczecin, Poland [ 123 ] Landspitali Natl Univ Hosp Iceland, IS-101 Reykjavik, Iceland [ 124 ] Univ Iceland, Fac Med, Sch Med, Sch Hlth Sci, IS-101 Reykjavik, Iceland [ 125 ] Nouvel Hop Civil, Hop Univ Strasbourg, Lab Diagnost Genet, F-67091 Strasbourg, France [ 126 ] Nouvel Hop Civil, Hop Univ Strasbourg, Serv Oncohematol, F-67091 Strasbourg, France [ 127 ] Univ Padua, Dept Surg Sci Oncol & Gastroenterol, Clin Surg 2, I-35124 Padua, Italy [ 128 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-35128 Padua, Italy [ 129 ] Portuguese Oncol Inst IPO PORTO, Dept Genet, P-4200072 Oporto, Portugal [ 130 ] Univ Porto, ICBAS, P-4050313 Oporto, Portugal [ 131 ] McGill Univ, Dept Human Genet & Oncol, Program Canc Genet, Montreal, PQ J2W 1S6, Canada [ 132 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 133 ] Mayo Clin, Dept Hlth Sci Res, Scottsdale, AZ 85259 USA [ 134 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 135 ] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10065 USA [ 136 ] Mem Sloan Kettering Canc Ctr, Clin Genet Res Lab, New York, NY 10065 USA [ 137 ] AKH Wien, Med Univ Vienna, Univ Klin Frauenheilkun, Comprehens Canc Ctr Vienna,Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 138 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA [ 139 ] Natl Israeli Canc Control Ctr, IL-34361 Haifa, Israel [ 140 ] Carmel Hosp, Dept Community Med & Epidemiol, Clalit Hlth Serv, IL-34361 Haifa, Israel [ 141 ] Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, IL-34362 Haifa, Israel [ 142 ] NN Petrov Oncol Res Inst, St Petersburg 197758, Russia [ 143 ] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON M5S 1A8, Canada [ 144 ] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1T8, Canada [ 145 ] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON M5G 2L7, Canada [ 146 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 147 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada [ 148 ] Dept Human Canc Genet, Columbus, OH 43210 USA [ 149 ] Ohio State Univ, Wexner Med Ctr, Dept Internal Med, Columbus, OH 43210 USA [ 150 ] Ohio State Univ, Wexner Med Ctr, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 151 ] Ohio State Univ, Arthur G James Canc Hosp, Ctr Comprehens Canc, Columbus, OH 43210 USA [ 152 ] Richard J Solove Res Inst OSUCCC James, Columbus, OH 43210 USA [ 153 ] Aalborg Univ Hosp, Dept Biochem, Sect Mol Diagnost, DK-9000 Aalborg, Denmark [ 154 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 155 ] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark [ 156 ] Azienda Osped Univ Pisana, Osped S Chiara, Div Anat Patol & Diagnost Mol & Ultrastrutturale, Lab Genet Oncol, I-56126 Pisa, Italy [ 157 ] Chaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Sheba Lab Mol Genet, IL-52621 Tel Hashomer, Israel [ 158 ] Inst Oncol, Rivka Ziv Med Ctr, IL-13100 Maimonides, Safed, Israel [ 159 ] Karolinska Univ Hosp, Dept Canc Genet, SE-17176 Stockholm, Sweden [ 160 ] Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden [ 161 ] Karolinska Univ Hosp, Dept Oncol Pathol, Radiumhemmet, S-17176 Stockholm, Sweden [ 162 ] Univ Lund Hosp, Dept Clin Sci, Div Oncol & Pathol, SE-22185 Lund, Sweden [ 163 ] Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, S-75185 Uppsala, Sweden [ 164 ] Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 165 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 166 ] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA [ 167 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA [ 168 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA [ 169 ] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Div Canc Med, Houston, TX 77230 USA [ 170 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Sir Peter MacCallum Dept Oncol, East Melbourne, Vic 3002, Australia [ 171 ] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia [ 172 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 173 ] INSERM, Inst Curie, Serv Genet Oncol, F-75248 Paris, France [ 174 ] Univ Paris 05, Fac Med, Sorbonne Paris Cite, F-75006 Paris, France [ 175 ] Univ Lyon 1, Fac Med Lyon Est, Genet Med, F-69373 Lyon 08, France [ 176 ] Ctr Leon Berard, Fdn Synergie Lyon Canc, Inst Natl Canc INCa, F-69008 Lyon 08, France [ 177 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 178 ] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL 33612 USA [ 179 ] Ctr Leon Berard, Hosp Civils Lyon, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon 08, France [ 180 ] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Duarte, CA 91010 USA, Human genetics, CCA - Oncogenesis, MUMC+: DA KG Lab Centraal Lab (9), Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, and Department of Medical and Clinical Genetics

Subjects
Genetic modifiers, Dna haplogroups, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], ADN mitocondrial, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Breast Cancer Family Registry, Brjóstakrabbamein, MULTIPLE, Aetiology, skin and connective tissue diseases, Phylogeny, Cancer, ddc:616, 0303 health sciences, Mutation, education.field_of_study, Variants, SINGLE-NUCLEOTIDE POLYMORPHISMS, Subclade, Mitochondrial DNA, 3. Good health, ddc, Damage, Oncology, Ovarian, 030220 oncology & carcinogenesis, DISEASES, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Single-nucleotide polymorphism, Breast Neoplasms/genetics, EMBRACE, GEMO Study Collaborators, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Genetics, Humans, education, Cancer och onkologi, Haplotype, BRCA2, Genes, mitochondrial haplogroup T1a1, breast cancer, BRCA2, Cancer and Oncology, GENETIC MODIFIERS, Polymorphisms, Cancer Research, [SDV]Life Sciences [q-bio], medicine.disease_cause, Haplogroup, 610 Medical sciences Medicine, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, 2.1 Biological and endogenous factors, OXIDATIVE STRESS, Non-U.S. Gov't, Medicine(all), Gen, BRCA1 Protein, Research Support, Non-U.S. Gov't, Cohort, OVARIAN, Mitochondria, Mitochondrial, Genes, Mitochondrial, Female, Research Article, Risk, Heterozygote, BRCA1 protein, breast neoplasms, female, genetic predisposition to disease, haplotypes, humans, phylogeny, risk, genes, BRCA2, genes, mitochondrial, heterozygote, mutation, cancer research, oncology, Population, 3122 Cancers, Oncology and Carcinogenesis, Breast Neoplasms, Biology, Research Support, Càncer de mama, Breast Cancer, medicine, Journal Article, Genetic Predisposition to Disease, ddc:610, Oncology & Carcinogenesis, HEBON, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CONSORTIUM, African, DNA HAPLOGROUPS, Arfgengi, Haplotypes, Susceptibility, BRCA1 Protein/genetics, Human mitochondrial DNA haplogroup
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects. European Commission Seventh Framework Program 223175: HEALTH-F2-2009-223175 Cancer Research UK C12292/A11174 C1287/A10118 C1287/A11990 C5047/A8385 National Health and Medical Research Council (NHMRC) program National Health and Medical Research Council (NHMRC) American Cancer Society Early Detection Professorship SIOP-06-258-01-COUN Intramural Research Program of the National Cancer Institute, National Institutes of Health National Cancer Institute, National Institutes of Health UM1 CA164920 Lithuania (BFBOCC-LT): Research Council of Lithuania LIG-07/2012 LSC 10.0010.08 European Social Fund 2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016 Liepaja City Council, Liepaja, Latvia Breast Cancer Research Foundation Cancer Association of South Africa (CANSA) Morris and Horowitz Families Professorship in Cancer Etiology and Outcomes Research NEYE Foundation Spanish Association against Cancer (Asociacion Espanola Contra el Cancer) AECC08 Thematic Network Cooperative Research in Cancer (Red Tematica Investigacion Cooperativa en Cancer (RTICC), Centro de Investigacion Cancer, Salamanca, Spain) RTICC 06/0020/1060 Spanish Ministry of Science and Innovation FIS PI08 1120 Fondo de Investigacion Sanitaria (FIS) SAF2010-20493 Fundacion Mutua Madrilena (FMMA) City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry (COH-CCGCRN) National Cancer Institute and the Office of the Director, National Institutes of Health RC4CA153828 Italian citizens Fondazione IRCCS Istituto Nazionale Tumori Italian Association for Cancer Research (AIRC) European Union (European Social Fund (ESF) Greek national funds through the "Education and Lifelong Learning" operational program of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA "Heracleitus II: Investing in knowledge society through the European Social Fund" Deutsches Krebsforschungszentrum (DKFZ) National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester, UK NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London University of Kansas Cancer Center P30 CA168524 Kansas Bioscience Authority Eminent Scholar Program Chancellors Distinguished Chair in Biomedical Sciences Professorship German Cancer Aid 109076 Center for Molecular Medicine Cologne (CMMC) Ligue National Contre le Cancer Association "Le cancer du sein, parlons-en!" Award Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program GOA BOF10/GOA/019 Ghent University Hospital National Cancer Institute grants to the GOG Administrative Office and Tissue Bank CA 27469 GOG Statistical and Data Center CA 37517 GOG's Cancer Prevention and Control Committee CA 101165 Instituto de Salud Carlos III (ISCIII), Madrid, Spain RD12/00369/0006 12/00539 European Regional Development Fund (Fonds europeen de developpement regional (FEDER)) funds Helsinki University Central Hospital Research Fund Academy of Finland 266528 Finnish Cancer Society Sigrid Juselius Foundation Dutch Cancer Society NKI1998-1854 NKI2004-3088 NKI2007-3756 Netherlands Organization of Scientific Research NWO 91109024 Pink Ribbon grant 110005 Biobanking and Molecular Resource Infrastructure (BBMRI) NWO 184.021.007/CP46 Hungarian Research and Technological Innovation Fund (KTIA)/Hungarian Scientific Research Fund (Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)) KTIA-OTKA CK-80745 KTIA-OTKA K-112228 Institut Catala d'Oncologia (ICO): contract grant sponsor: Asociacion Espanola Contra el Cancer Spanish Health Research Foundation Ramon Areces Foundation Instituto de Salud Carlos III (ISCIII) Catalan Health Institute Autonomous Government of Catalonia International Hereditary Cancer Center (Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland) PBZ_KBN_122/P05/2004 Icelandic Association "Walking for Breast Cancer Research" Landspitali University Hospital Research Fund Canadian Institutes of Health Research (CIHR) for the "CIHR Team in Familial Risks of Breast Cancer" program, Canadian Breast Cancer Research Alliance 019511 Ministry of Economic Development, Innovation and Export Trade PSR-SIIRI-701 Ministero della Salute and a "5 x 1,000" Istituto Oncologico Veneto grant Liga Portuguesa Contra o Cancro National Breast Cancer Foundation Queensland Cancer Fund Cancer Councils of New South Wales, Victoria, Tasmania and South Australia Cancer Foundation of Western Australia National Institutes of Health (NIH) through the National Cancer Institute (NCI) CA 116167 CA 128978 CA 176785 NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer CA116201 US Department of Defense Ovarian Cancer Idea award W81XWH-10-1-0341 Ministry of Health of the Czech Republic to Masaryk Memorial Cancer Institute MMCI 00209805 European Regional Development Fund State Budget of the Czech Republic (RECAMO) CZ. 1.05/2.1.00/03.0101 Charles University in Prague project UNCE204024 Robert and Kate Niehaus Clinical Cancer Genetics Initiative Intramural Research Program of the National Cancer Institute Westat, Inc, Rockville, MD, USA N02-CP-11019-50 N02-CP-65504 Clalit Health Services in Israel Israel Cancer Association Breast Cancer Research Foundation (BCRF), New York, NY, USA Russian Federation for Basic Research 11-04-00227 12-04-00928 12-04-01490 Federal Agency for Science and Innovations, Russia 02.740.11.0780 Ohio State University Comprehensive Cancer Center Istituto Toscano Tumori (ITT) Israeli Inherited Breast Cancer Consortium Swedish Breast Cancer Swedish Cancer Society Ralph and Marion Falk Medical Research Trust Entertainment Industry Fund National Women's Cancer Research Alliance University of California, Los Angeles Jonsson Comprehensive Cancer Center Foundation: Breast Cancer Research Foundation University of California, San Francisco Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center Cancer Research UK University of Pennsylvania: National Institutes of Health (NIH) R01 CA102776 R01 CA083855 Susan G Komen for the Cure, Basser Center for BRCA Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation 5U01 CA113916 R01 CA140323 ISCIIIRETIC RD06/0020/1051 PI09/02483 PI10/01422 PI10/00748 PI13/00285 PI13/00189 2009SGR290 PI13/00189 2009SGR283 CA125183 R01 CA142996 1U01CA161032

Published
2015

10. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author

Gaudet, Mia M., Kuchenbaecker, Karoline B., Vijai, Joseph, Klein, Robert J., Kirchhoff, Tomas, McGuffog, Lesley, Barrowdale, Daniel, Dunning, Alison M., Lee, Andrew, Dennis, Joe, Healey, Sue, Dicks, Ed, Soucy, Penny, Sinilnikova, Olga M., Pankratz, Vernon S., Wang, Xianshu, Eldridge, Ronald C., Tessier, Daniel C., Vincent, Daniel, Bacot, Francois, Hogervorst, Frans B.L., Peock, Susan, Stoppa-Lyonnet, Dominique, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Peterlongo, Paolo, Schmutzler, Rita K., Nathanson, Katherine L., Piedmonte, Marion, Singer, Christian F., Thomassen, Mads, Sokolowska, Johanna, Bronner, Myriam, Hansen, Thomas V.O., Neuhausen, Susan L., Blanco, Ignacio, Greene, Mark H., Garber, Judith, Weitzel, Jeffrey N., Andrulis, Irene L., Goldgar, David E., D'Andrea, Emma, Caldes, Trinidad, Nevanlinna, Heli, Osorio, Ana, van Rensburg, Elizabeth J., Arason, Adalgeir, Rennert, Gad, van den Ouweland, Ans M.W., van der Hout, Annemarie H., Kets, Carolien M., Aalfs, Cora M., Wijnen, Juul T., Ausems, Margreet G.E.M., Frost, Debra, Ellis, Steve, Fineberg, Elena, Platte, Radka, Evans, D. Gareth, Jacobs, Chris, Adlard, Julian, Tischkowitz, Marc, Porteous, Mary, Damiola, Francesca, Golmard, Lisa, Barjhoux, Laure, Longy, Michel, Belotti, Muriel, Ferrer, Sandra Fert, Mazoyer, Sylvie, Spurdle, Amanda B., Manoukian, Siranoush, Barile, Monica, Genuardi, Maurizio, Arnold, Norbert, Meindl, Alfons, Sutter, Christian, Wappenschmidt, Barbara, Domchek, Susan M., Pfeiler, Georg, Friedman, Eitan, Jensen, Uffe Birk, Robson, Mark, Shah, Sohela, Lazaro, Conxi, Mai, Phuong L., Benitez, Javier, Southey, Melissa C., Schmidt, M. K., Fasching, Peter A., Peto, Julian, Humphreys, Manjeet K., Wang, Qin, Michailidou, Kyriaki, Sawyer, Elinor J., Burwinkel, Barbara, Guénel, Pascal, Bojesen, Stig E., Milne, Roger L., Brenner, Hermann, Lochmann, Magdalena, Brauch, Hiltrud, Ko, Yon Dschun, Baisch, Christian, Fischer, Hand Peter, Bruening, Thomas, Pesch, Beate, Rabstein, Sylvia, Spickenheuer, Anne, Aittomäki, Kristiina, Dörk, Thilo, Margolin, Sara, Mannermaa, Arto, Lambrechts, Diether, Chang-Claude, Jenny, Radice, Paolo, Giles, Graham G., Haiman, Christopher A., Winqvist, Robert, Devillee, Peter, García-Closas, Montserrat, Schoof, Nils, Hooning, M. J., Cox, Angela, Pharoah, Paul D.P., Jakubowska, Anna, Orr, Nick, González-Neira, Anna, Pita, Guillermo, Alonso, M. Rosario, Hall, Per, Couch, Fergus J., Simard, Jacques, Altshuler, David, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Offit, Kenneth, Rookus, M. A., van Leeuwen, F. E., Verhoef, S., de Lange, J. L., Collée, J. M., Seynaeve, C., van Deurzen, C. H.M., van Asperen, C. J., Tollenaar, R. A., Devilee, P., van Cronenburg, T. C.T.E.F., Mensenkamp, A. R., van der Luijt, R. B., van Os, T. A.M., Gille, J. J.P., Waisfisz, Q., Meijers-Heijboer, H. E.J., Gómez-Garcia, E. B., Blok, M. J., Oosterwijk, J. C., Mourits, M. J., de Bock, G. H., Vasen, H. F., Miedzybrodzka, Zosia, Gregory, Helen, Morrison, Patrick, Jeffers, Lisa, Cole, Trevor, Ong, Kai ren, Hoffman, Jonathan, Donaldson, Alan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Rogers, Mark T., McCann, Emma, Kennedy, M. John, Barton, David, Drummond, Sarah, Brewer, Carole, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Davidson, Rosemarie, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Izatt, Louise, Langman, Caroline, Brady, Angela, Dorkins, Huw, Melville, Athalie, Randhawa, Kashmir, Barwell, Julian, Serra-Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Side, Lucy, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Douglas, Fiona, Claber, Oonagh, Collier, Rebecca, Jobson, Irene, Walker, Lisa, McLeod, Diane, Durell, Sarah, Stayner, Barbara, Eeles, Rosalind A., Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern-Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Cook, Jackie, Quarrell, Oliver, Bardsley, Cathryn, Hodgson, Shirley, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Eccles, Diana, Lucassen, Anneke, Crawford, Gillian, McBride, Donna, Smalley, Sarah, Sinilnikova, Olga, Verny-Pierre, Carole, Giraud, Sophie, Léone, Mélanie, Gauthier-Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Tirapo, Carole, de Pauw, Antoine, Bressac-de-Paillerets, Brigitte, Caron, Olivier, Bignon, Yves Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Handallou, Sandrine, Hardouin, Agnés, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Rouleau, Etienne, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Dreyfus, Hélène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Frénay, Marc, Vénat-Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Lynch, Henry T., Snyder, Carrie L., Clinical Genetics, Medical Oncology, Human Genetics, Human genetics, EMGO - Quality of care, Anesthesiology, CCA - Oncogenesis, CCA - Cancer biology and immunology, Epidemiology and Data Science, Department of Obstetrics and Gynecology, Clinicum, and Department of Medical and Clinical Genetics

Subjects
Cancer Research, SUSCEPTIBILITY ALLELES, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], QH426-470, Settore MED/03 - GENETICA MEDICA, Genoma humà, SUBTYPES, Breast cancer, 0302 clinical medicine, Risk Factors, CDKN2A, Genotype, BRCA2 MUTATION CARRIERS, Malalties hereditàries, GWAS, skin and connective tissue diseases, Genetics (clinical), POPULATION, 2. Zero hunger, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, COMMON VARIANTS, genetic modifiers, BRCA2, cancer risk, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, Genetic diseases, Adult, Heterozygote, Medizinische Fakultät -ohne weitere Spezifikation, education, Population, Breast Neoplasms, Single-nucleotide polymorphism, Locus (genetics), Human chromosomes, Biology, Polymorphism, Single Nucleotide, OVARIAN-CANCER, BRCA2-specific modifier locus at 6p24, Càncer de mama, 03 medical and health sciences, TRANSCRIPTION FACTOR AP-2, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Allele, GENOME-WIDE ASSOCIATION, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, Aged, 030304 developmental biology, BRCA2 Protein, Cromosomes humans, Human genome, Hereditary cancer and cancer-related syndromes [ONCOL 1], CONSORTIUM, medicine.disease, Mutation, 3111 Biomedicine, ZNF365, Genome-Wide Association Study
Abstract

Contains fulltext : 118578.pdf (Publisher’s version ) (Open Access) Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013

11. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Author

Ruark, Elise, Snape, Katie, Humburg, Peter, Loveday, Chey, Bajrami, Ilirjana, Brough, Rachel, Rodrigues, Daniel Nava, Renwick, Anthony, Seal, Sheila, Ramsay, Emma, Duarte, Silvana Del Vecchio, Rivas, Manuel A, Warren-Perry, Margaret, Zachariou, Anna, Campion-Flora, Adriana, Hanks, Sandra, Murray, Anne, Ansari Pour, Naser, Douglas, Jenny, Gregory, Lorna, Rimmer, Andrew, Walker, Neil M, Yang, Tsun-Po, Adlard, Julian W, Barwell, Julian, Berg, Jonathan, Brady, Angela F, Brewer, Carole, Brice, Glen, Chapman, Cyril, Cook, Jackie, Davidson, Rosemarie, Donaldson, Alan, Douglas, Fiona, Eccles, Diana, Evans, D Gareth, Greenhalgh, Lynn, Henderson, Alex, Izatt, Louise, Kumar, Ajith, Lalloo, Fiona, Miedzybrodzka, Zosia, Morrison, Patrick J, Paterson, Joan, Porteous, Mary, Rogers, Mark T, Shanley, Susan, Walker, Lisa, Gore, Martin, Houlston, Richard, Brown, Matthew A, Caufield, Mark J, Deloukas, Panagiotis, McCarthy, Mark I, Todd, John A, Breast and Ovarian Cancer Susceptibility Collaboration, Wellcome Trust Case Control Consortium, Turnbull, Clare, Reis-Filho, Jorge S, Ashworth, Alan, Antoniou, Antonis C, Lord, Christopher J, Donnelly, Peter, and Rahman, Nazneen

Subjects
General Science & Technology, Breast Neoplasms, Rare Diseases, Breast Cancer, Phosphoprotein Phosphatases, Humans, Cluster Analysis, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Lymphocytes, Aetiology, Alleles, Cancer, Ovarian Neoplasms, Mosaicism, DNA, Exons, Breast and Ovarian Cancer Susceptibility Collaboration, Ovarian Cancer, Isoenzymes, Protein Phosphatase 2C, Mutation, Wellcome Trust Case Control Consortium, Female, Tumor Suppressor Protein p53, Sequence Analysis
Abstract

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Published
2013

Catalog

Books, media, physical & digital resources
See catalog results